2. Academic Validation
  3. TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer

TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer

  • Cancer Lett. 2026 Mar 31:641:218271. doi: 10.1016/j.canlet.2026.218271.
Yuan Huang 1,  Chen Chen 1,  Mingqiang Su 2,  Wanteng Ye 1,  Shu Wei 1,  Kuangye Long 1,  Yunjie Huang 1,  Haiyong Chen 3,  Zhangfeng Zhong 4,  Lina Hou 5,  Jinge Zhang 6,  Wanlong Tan 7,  Fei Li 8
Affiliations

Affiliations

  • 1 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
  • 2 Department of Urology, Zigong Fourth People's Hospital, Sichuan, 643000, PR China.
  • 3 School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong R619, 3 Sassoon Road, Pokfulam, 999077, Hong Kong, China.
  • 4 Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, PR China.
  • 5 Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
  • 6 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, PR China; Department of Urology, Baoshan People's Hospital, Baoshan, Yunnan, 678000, PR China. Electronic address: [email protected].
  • 7 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, PR China. Electronic address: [email protected].
  • 8 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, PR China. Electronic address: [email protected].
PMID: 41570932 DOI: 10.1016/j.canlet.2026.218271
Abstract

Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder Cancer (BCa), yet only 35 % of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA Sequencing, together with assay for transposase-accessible chromatin using Sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated Mitophagy and Apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired Mitophagy flux, leading to enhanced survival of Cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.

Keywords

Bladder cancer; Cisplatin resistance; Mitophagy; TMEM11.

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